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Role of CD8-positive cells in radioimmunotherapy utilizing (177)Lu-mAbs in an immunocompetent rat colon carcinoma model.

Elgström E, Eriksson SE, Ohlsson TG, Nilsson R, Tennvall J - EJNMMI Res (2015)

Bottom Line: Five animals in the group given anti-CD8 + RIT were sacrificed due to metastatic disease, and 4 additional animals were found to have metastases at autopsy.In the group given RIT, 4 animals developed metastatic disease, but no metastases were found in the remaining 11 animals at autopsy.The initial depletion of CD8-positive cells in our syngeneic rat colon carcinoma model resulted in a higher frequency of animals developing metastases.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Barngatan 2B, SE-221 85 Lund, Sweden.

ABSTRACT

Background: CD8-positive cells might play a crucial role in the therapeutic response to radiation, which has however not been investigated in radioimmunotherapy (RIT). The aim of this study was to evaluate whether cytotoxic T cells affect the response of established tumors and, above all, if they delay or prevent the development of distant metastases after RIT, using an immunocompetent syngeneic rat colon carcinoma model.

Methods: The cytotoxic T cells were depleted in 15 rats by anti-CD8 before the injection of the radioimmunoconjugate (400 MBq/kg body weight (177)Lu-BR96, which binds to the tumor-associated antigen Lewis Y). Fifteen other rats were treated with RIT only. Both groups were followed for 99 days. Blood samples were collected at least once weekly, and tumors were monitored twice weekly.

Results: Twenty-nine of the 30 animals exhibited local complete response. The non-responder was treated with anti-CD8 and RIT but succumbed later due to metastases. Five animals in the group given anti-CD8 + RIT were sacrificed due to metastatic disease, and 4 additional animals were found to have metastases at autopsy. In the group given RIT, 4 animals developed metastatic disease, but no metastases were found in the remaining 11 animals at autopsy. Thus, at the end of the study, 6 animals in the anti-CD8 + RIT group were free from metastases, while 11 were free from metastases in the group receiving RIT. CD3(+)CD4(-)CD8(+) lymphocytes were consistently depleted by the anti-CD8 treatment. The myelosuppression was otherwise similar in the two groups. The initial depletion of CD8-positive cells in our syngeneic rat colon carcinoma model resulted in a higher frequency of animals developing metastases.

Conclusions: Depletion of CD8-positive cells during RIT in an immunocompetent rat tumor model might influence the number of animals developing metastases, indicating that the immune system may be important in the long-term outcome of RIT.

No MeSH data available.


Related in: MedlinePlus

Curve of metastatic disease. Fraction of rats with observed metastatic disease in RIT (solid line) and anti-CD8 + RIT group (dashed line) during the study period including results of autopsy at the end of the study. Day 0 = day for injection of 177Lu-DOTA-BR96 treatment.
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Fig2: Curve of metastatic disease. Fraction of rats with observed metastatic disease in RIT (solid line) and anti-CD8 + RIT group (dashed line) during the study period including results of autopsy at the end of the study. Day 0 = day for injection of 177Lu-DOTA-BR96 treatment.

Mentions: Five of the 15 animals in the anti-CD8 + RIT group were sacrificed due to loss of body weight (on days 28, 42, 45, 91, and 96), and metastases were verified in all these animals at subsequent autopsy. The autopsy performed at the end of the study revealed metastases in 4 additional animals, but the remaining 6 animals were free from detectable metastases. Four of the 15 animals in the RIT group were sacrificed due to loss of body weight (on days 56, 84, 91, and 91), metastases being verified at autopsy. All the remaining animals in this group were free from detectable metastases at the end of the study (there were no significant difference between the two groups, Mantel-Cox test p = 0.11); in the RIT group, it is expected to find metastases up to 100 days after administration of radioimmunoconjugate according to our previous study [21], indicating that metastases do not develop later. Thus, 99 days after injection of the radioimmunoconjugate, 11 animals in the RIT group were free from detectable metastases, while only 6 were free from detectable metastases in the anti-CD8 + RIT group (Figure 2, Table 1).Figure 2


Role of CD8-positive cells in radioimmunotherapy utilizing (177)Lu-mAbs in an immunocompetent rat colon carcinoma model.

Elgström E, Eriksson SE, Ohlsson TG, Nilsson R, Tennvall J - EJNMMI Res (2015)

Curve of metastatic disease. Fraction of rats with observed metastatic disease in RIT (solid line) and anti-CD8 + RIT group (dashed line) during the study period including results of autopsy at the end of the study. Day 0 = day for injection of 177Lu-DOTA-BR96 treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385015&req=5

Fig2: Curve of metastatic disease. Fraction of rats with observed metastatic disease in RIT (solid line) and anti-CD8 + RIT group (dashed line) during the study period including results of autopsy at the end of the study. Day 0 = day for injection of 177Lu-DOTA-BR96 treatment.
Mentions: Five of the 15 animals in the anti-CD8 + RIT group were sacrificed due to loss of body weight (on days 28, 42, 45, 91, and 96), and metastases were verified in all these animals at subsequent autopsy. The autopsy performed at the end of the study revealed metastases in 4 additional animals, but the remaining 6 animals were free from detectable metastases. Four of the 15 animals in the RIT group were sacrificed due to loss of body weight (on days 56, 84, 91, and 91), metastases being verified at autopsy. All the remaining animals in this group were free from detectable metastases at the end of the study (there were no significant difference between the two groups, Mantel-Cox test p = 0.11); in the RIT group, it is expected to find metastases up to 100 days after administration of radioimmunoconjugate according to our previous study [21], indicating that metastases do not develop later. Thus, 99 days after injection of the radioimmunoconjugate, 11 animals in the RIT group were free from detectable metastases, while only 6 were free from detectable metastases in the anti-CD8 + RIT group (Figure 2, Table 1).Figure 2

Bottom Line: Five animals in the group given anti-CD8 + RIT were sacrificed due to metastatic disease, and 4 additional animals were found to have metastases at autopsy.In the group given RIT, 4 animals developed metastatic disease, but no metastases were found in the remaining 11 animals at autopsy.The initial depletion of CD8-positive cells in our syngeneic rat colon carcinoma model resulted in a higher frequency of animals developing metastases.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Barngatan 2B, SE-221 85 Lund, Sweden.

ABSTRACT

Background: CD8-positive cells might play a crucial role in the therapeutic response to radiation, which has however not been investigated in radioimmunotherapy (RIT). The aim of this study was to evaluate whether cytotoxic T cells affect the response of established tumors and, above all, if they delay or prevent the development of distant metastases after RIT, using an immunocompetent syngeneic rat colon carcinoma model.

Methods: The cytotoxic T cells were depleted in 15 rats by anti-CD8 before the injection of the radioimmunoconjugate (400 MBq/kg body weight (177)Lu-BR96, which binds to the tumor-associated antigen Lewis Y). Fifteen other rats were treated with RIT only. Both groups were followed for 99 days. Blood samples were collected at least once weekly, and tumors were monitored twice weekly.

Results: Twenty-nine of the 30 animals exhibited local complete response. The non-responder was treated with anti-CD8 and RIT but succumbed later due to metastases. Five animals in the group given anti-CD8 + RIT were sacrificed due to metastatic disease, and 4 additional animals were found to have metastases at autopsy. In the group given RIT, 4 animals developed metastatic disease, but no metastases were found in the remaining 11 animals at autopsy. Thus, at the end of the study, 6 animals in the anti-CD8 + RIT group were free from metastases, while 11 were free from metastases in the group receiving RIT. CD3(+)CD4(-)CD8(+) lymphocytes were consistently depleted by the anti-CD8 treatment. The myelosuppression was otherwise similar in the two groups. The initial depletion of CD8-positive cells in our syngeneic rat colon carcinoma model resulted in a higher frequency of animals developing metastases.

Conclusions: Depletion of CD8-positive cells during RIT in an immunocompetent rat tumor model might influence the number of animals developing metastases, indicating that the immune system may be important in the long-term outcome of RIT.

No MeSH data available.


Related in: MedlinePlus